Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity

Nat Commun. 2019 Aug 21;10(1):3773. doi: 10.1038/s41467-019-11728-2.

Abstract

Neoantigen burden is a major determinant of tumor immunogenicity, underscored by recent clinical experience with checkpoint blockade therapy. Yet the majority of patients do not express, or express too few, neoantigens, and hence are less responsive to immune therapy. Here we describe an approach whereby a common set of new antigens are induced in tumor cells in situ by transient downregulation of the transporter associated with antigen processing (TAP). Administration of TAP siRNA conjugated to a broad-range tumor-targeting nucleolin aptamer inhibited tumor growth in multiple tumor models without measurable toxicity, was comparatively effective to vaccination against prototypic mutation-generated neoantigens, potentiated the antitumor effect of PD-1 antibody or Flt3 ligand, and induced the presentation of a TAP-independent peptide in human tumor cells. Treatment with the chemically-synthesized nucleolin aptamer-TAP siRNA conjugate represents a broadly-applicable approach to increase the antigenicity of tumor lesions and thereby enhance the effectiveness of immune potentiating therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / immunology*
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines
  • Cell Line, Tumor
  • Down-Regulation
  • Epitopes / immunology
  • Female
  • Humans
  • Immunization
  • Immunogenicity, Vaccine
  • Immunotherapy*
  • Male
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • NIH 3T3 Cells
  • Neoplasms / immunology*
  • Neoplasms / prevention & control*
  • Neoplasms, Experimental
  • Oligodeoxyribonucleotides
  • Phosphoproteins
  • Programmed Cell Death 1 Receptor / immunology
  • RNA, Small Interfering / administration & dosage
  • RNA-Binding Proteins
  • Spleen / immunology
  • Spleen / pathology
  • Vaccination

Substances

  • AGRO 100
  • ATP-Binding Cassette Transporters
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Epitopes
  • Membrane Proteins
  • Oligodeoxyribonucleotides
  • PDCD1 protein, human
  • Phosphoproteins
  • Programmed Cell Death 1 Receptor
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • flt3 ligand protein
  • nucleolin
  • transporter associated with antigen processing (TAP)